EP0742208A1 - Dérivés de 2-ureido-benzamide - Google Patents
Dérivés de 2-ureido-benzamide Download PDFInfo
- Publication number
- EP0742208A1 EP0742208A1 EP95401049A EP95401049A EP0742208A1 EP 0742208 A1 EP0742208 A1 EP 0742208A1 EP 95401049 A EP95401049 A EP 95401049A EP 95401049 A EP95401049 A EP 95401049A EP 0742208 A1 EP0742208 A1 EP 0742208A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- benzamide
- diphenylmethylpiperidin
- alkyl
- heptylureido
- ureido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to a novel 2-ureido-benzamide derivative having potent acyl coenzyme A:cholesterol acyltransferase(ACAT; EC2.3.1.26) inhibiting activity, to pharmaceutical composition containing these compounds and to use thereof for the treatment and prevention of atherosclerosis.
- Ischemic circulatory diseases such as myocardial infarction and cerebral infarction resulting from atherosclerosis have been a major cause of human death.
- the studies on atherosclerosis have been carried out in the various fields for long years.
- ACAT esterification of intracellar cholesterol is effectively catalyzed by the enzyme: ACAT which is found later in various tissues such as liver, intestine, adrenal and macrophages. It is said that ACAT may be present in all tissues [The Enzymes, 16 , 523-539 (1983)].
- ACAT plays a key role in the gastrointestinal absorption of cholesterol.
- dietary and biliary cholesterol derived from the diet and biosynthesis must be esterified by the action of ACAT before it can be incorporated into the chyromicron particules which are then released into the blood stream [Eur. J. Clin. Invest., 9 , 55 (1971)].
- inhibition of ACAT in intestinal mucosa appears to block intestinal absorption of cholesterol, resulting in the decrease of blood cholesterol level.
- such an intestinal ACAT inhibitor may involve unfavorable increase of the endogeneous cholesterol synthesis and possible ineffectiveness of such inhibitor on patients having no hyper-function in cholesterol absorption.
- ACAT may participate in the synthesis and secretion of VLDL and the control of biliary excretion of cholesterol [J. Lipid Res., 26 , 647 (1985)] and inhibition of the liver ACAT may result in lowering of the blood lipid level.
- Cholesterol esters are a major component of atherosclerotic lesions and also a major storage form of cholesterol in arterial wall cells. Accumulation of cholesterol esters is linked to the form cell formation which is catalyzed by ACAT in macrophages. Thus, inhibition of the macrpohage ACAT may prevent directly the progression of atherosclerotic lesion formation by decreasing the form cell formation without unfavorable effects as in the case of ACAT inhibition in intestine.
- the present inventors synthesized various novel 2-ureido-benzamide compounds having substituents on both of amide and urea(ureido) nitrogen atoms and intensively investigated their activities, and, as the result, found that the compounds have excellent ACAT inhibitory activity and are expected to be useful as a drug for atherosclesosis and related diseases.
- the present invention provides
- halogen is fluorine(F), chlorine(Cl) or bromine(Br) and the terms "alkyl”, “alkoxy” and “alkanoyl” mean straight- and branched-chain alkyl, alkoxy and alkanoyl, respectively.
- (C 1 -C 4 )alkyl is methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl;
- (C 1 -C 4 )alkylsulfonyl and (C 1 -C 4 )alkylcarbonyl are sulfonyl and carbonyl substituted by such (C 1 -C 4 )alkyl, respectively;
- (C 1 -C 4 )alkoxy is methoxy, ethoxy, n- or iso-propoxy or n-, iso-, sec- or tert-butoxy;
- (C 1 -C 4 )alkoxycarbonyl is carbonyl substituted by such (C 1 -C 4 )alkoxy;
- (C 1 -C 4 )alkanoyl is acetyl,propionyl or n- or iso-butyryl.
- Alkyl higher than C 4 such as (C 5 -C 15 )alkyl may be represented by pentyl(C 5 ), hexyl(C 6 ), heptyl(C 7 ), octyl(C 8 ), nonyl(C 9 ), decyl(C 10 ), undecyl(C 11 ), dodecyl(C 12 ), tridecyl(C 13 ), tetradecyl(C 14 ), pentadecyl(C 15 ) and their branched-chain form.
- Preferred embodiments of this invention represented by the formula(1) exhibit one or more of the following features; (a) R 1 is H and R 2 is H or di-substituted amino group; (b) X is (C 3 -C 10 )alkyl, more preferably, (C 4 -C 8 )alkyl; and/or (c) Y is H and Z is (N-aralkyl)aminoalkyl group such as (N-diphenylmethyl)piperidy group with or without intermediary alkylene chain between nitrogen atom of the amide and the piperidyl ring; or Y and Z are combined to form a ring such as (N-diphenylmethyl)piperazinyl ring.
- Preferred example of the compounds(1) includes:
- the above compounds(1) may be in the form of its pharmaceutical acceptable acid addition salts which are included within the scope of this invention.
- Preferred example of the salts include salts with inorganic and organic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, tartaric, citric, fumaric, malic, maleic, succinic, methanesulfonic, benzenesulfonic and p-toluenesulfonic acids.
- Preparation of the salts can be carried out in accordance with well known techniques for forming salts.
- This invention also relates to a method of or use for reducing the cholesterol content of the arterial walls and treating atherosclerosis and related diseases of mammals which comprises administrating to said mammals an effective amount of a compound as recited above.
- the compounds(1) have potent ACAT inhibiting activity with weak toxicity as shown in the following test example.
- ACAT catalyzes the esterification cholesterol with higher fatty acids and it plays an important role in the absorption of cholesterol and in the intracellular accumulation of cholesterol esters.
- ACAT inhibitor can reduce absorption of dietary cholesterol and intracellular cholesterol ester accumulation in the arterial wall, thereby, lowering the blood cholesterol level with retarding the build-up of atherosclerotic lesions.
- the compounds(1) of this invention are useful as safe prophylactic and therapeutic agents for hypercholesterolemia, atherosclerosis and diseases resulting from these (e.g. ischemic heart diseases such as myocardial infarction, cerebrovascular diseases such as cerebral infarction and cerebral apoplexy) in mammals (e.g. mouse, rat, rabbit, dog, monkey, human).
- ischemic heart diseases such as myocardial infarction, cerebrovascular diseases such as cerebral infarction and cerebral apoplexy
- mammals e.g. mouse, rat, rabbit, dog, monkey, human.
- compositions which comprise an effective anti-atherosclerotic amount of a compound as recited above.
- the compounds of formula(1) are preferably presented with pharmaceutically acceptable appropriate carriers, excipients or diluents as pharmaceutical formulations such as powders, granules, tablets, capsules or injections, which can be prepared by any of the well known techniques of pharmacy and administrated either orally or non-orally.
- the oral route of administration may be preferred.
- the amount of a compound of formula(1) which is required m achieve the desired biological effect will, of course, depend on the kind of compound(1), the mode of administration, the clinical condition and age of the recipient and the other factors.
- a daily dose per kilogram of body weight is expected to lie in the range of from 10 ⁇ g to 10mg, typically from 50 ⁇ g to 50mg, and such daily dose is preferably administrated as a single dose or in two or three divided doses.
- This invention still further relates to process for preparing compounds as recited above.
- the desired compounds(1) thus obtained can be purified and recovered by using per se known separation or purification procedures (e. g. concentration, solvent extraction, column chromatography, recrystallization).
- ACAT enzyme fraction was prepared from microsome of human derived hepatoma Hep G2 cell according to Sandra's method [Journal of Lipid Research 27 , 875 (1986)].
- Microsome was suspended at a concentration of 200 ⁇ g protein/ 20 ⁇ l in 0.1 M phosphate buffer solution(pH7.4) and the suspension was preincubated at 37°C for 5 minutes after addition of 10 ⁇ l of each test compound dissolved in 0.1M phosphate buffer solution containing bovine serum albmin(BSA). Then, the reaction was initiated by the addition of 5nmoles of labeled [ 14 C]-oleoyl-CoA dissolved in 20 ⁇ l of the said phosphate buffer solution containing BSA and the reaction was stopped by the addition of 20 ⁇ l of 2N HCl after 10 minutes. [ 14 C] cholesterol-oleate formed was separated by thin-layer chromatography and the radioactivity was counted with liquid scintillation counter.
- ACAT inhibitory activities of the test compounds were shown as IC 50 values.
- Intracellular [ 14 C] cholesterol-oleate formed was separated by thin-layer chromatography and the radioactivity was counted with lipid scintillation counter.
- ACAT inhibitory activities of the test compounds were shown as IC 50 values.
- mice Male mice were fed a standard powder diet containing the test compounds for 16 days. After 14 and 15 days on this diet, aggregated-LDL (containing 4mg cholesterol) prepared from LDL receptor deficient KHC rabbit and [ 14 C]oleic acid together with the said aggregated-LDL (containing 0.5mg cholesterol) were injected into the peritoneal cavity of these animals, respectively. After 16 days on this treatment, peritoneal macrophages were harvested by peritoneal lavage with PBS solution and CHCl 3 -MeOH(2:1) were added to the cell suspension in order to extract lipids. Formed [ 14 C]cholesterol oleate was separated by thin-layer chromatography and the radioactivity was counted.
- aggregated-LDL containing 4mg cholesterol
- [ 14 C]oleic acid together with the said aggregated-LDL (containing 0.5mg cholesterol) were injected into the peritoneal cavity of these animals, respectively.
- peritoneal macrophages were harvested by peritoneal lavage
- ACAT inhibitory activities of the test compounds were shown as inhibiting percentage referred to control group.
- Acute toxicity Nine compounds(Example No. 1, 2, 5, 6, 12, 19, 28, 31 and 45) were tested by using male ICR strain mouse weighing 23.0 ⁇ 0.7g. Each test compound was suspended with 0.5% CMC-Na and orally administered in a dose of 1000mg/10ml/kg of body weight, and general signs were observed for seven days. Seven days after administration of each test compounds, no macroscopic changes were observed on any organs at autopsy.
- Preparation 1 to 11 are described for synthesis of the amine (8) and Preparation 12 to 20 are described for synthesis of the 2-amino-benzamide(2), both of which are intermediates for the preparation of the objective 2-ureido-benzamide(1).
- 2-amino-5-fluoro-N-(1-diphenylmethylpiperidin-4-yl)benzamide was prepared from 5-fluoro-2-nitrobenzoic acid and 4-amino-1-diphenylmethylpiperidine.
- n-Heptylamine (2.3g, 20.2mmol) was added to a solution of the carbamate described above in dichloromethane (50ml). The mixture was refluxed for 3 hours and then concentrated. The residue was purified by column chromatography on silica gel to give 2-(N'-n-heptylureido)-5-dimethylamino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (1.8g, 62.0%): mp 178-179 °C; 1 H NMR (DMSO-d 6 ) 0.86 (3H, t), 1.14-1.47 (12H, m), 1.50-1.68 (3H, m), 1.79 (2H, t), 2.70-2.89 (8H, m), 2.97 (2H, dt), 3.14 (2H, t), 4.27 (1H, s), 6.78-6.90 (3H, m), 7.13-7.41 (10H, m), 7.85 (1H, d), 8.
- Example 2 to 26 were prepared from other appropriately substituted 2-amino-benzamide and other appropriately substituted amine which were described in braces: ⁇ after title of these compounds.
- Phenyl chloroformate (5.0ml, 40mmol) was added to a solution of 2-amino-N-(1-benzylpiperidin-4-yl)benzamide (3.1g, 10mmol) in chloroform (50ml). The mixture was refluxed for 2 hours. After cooling, ether was added and then the solution was washed with saturated NaHCO 3 solution and brine. The organic layer was concentrated to give 2-phenoxy carbonylamino-N-(1-phenoxylcarbonylpiperidin-4-yl)benzamide.
- Example 29 to 42 were prepared from other appropriately substituted 2-amino-benzamide and other appropriately substituted carboxylic acid which were described in braces: ⁇ after titles of these compounds.
- Example44 The following compound (Example44) was prepared in a similar manner, but replacing N-(1-benzylpiperidin-4-yl)-2-(N'-n-heptylureido)benzamide with N-(1-benzylpiperidin-4-yl)-2-(N'-n-octylureido)benzamide.
- Methanesulfonyl chloride (0.05ml, 0.65mmol) was added dropwise to a solution of triethylamine (0.09ml, 0.6mmol) and 2-(N'-n-heptylureido)-5-amino-N-(1-diphenylmethylpiperidin-4-yl)benzamide (0.32g, 0.59mmol) in dichloromethane (15ml) at 0 °C. The mixture was stirred for 24 hours and then concentrated.
- Triethylamine (0.098ml, 0.65mmol) and acetic anhydride (0.067ml, 0.07mmol) were added to a solution of the 2-(N'-n-heptylureido)-5-amino-N-(1-diphenylmethylpiperidin-4-yl)benzamide (0.32g, 0.59mmol) in dichloromethane (3ml) at room temperature. The mixture was stirred for 24 hours and then concentrated.
- Example 61 The following compound (Example 61) was prepared in a similar manner, but replacing n-butyraldehyde with acetone.
- Example 62 and 63 illustrate pharmaceutical compositions according to the present invention and an "active ingredient" in these Examples is any compound of the formula(1) as hereinabove defined, preferably one of the compounds of Examples 1 to 61.
- Tablet formulation Tablets each containing 100mg of active ingredient, 200mg of lactose, 40mg of cellulose and 5mg of magnesium stearate were prepared in accordance with usual procedure.
- Hard-shell gelatin capsules each containing 50mg of active ingredient, 100mg of lactose, 30mg of cornstarch and 2mg of magnesium stearate were prepared in accordance with usual procedure.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95401049A EP0742208A1 (fr) | 1995-05-05 | 1995-05-05 | Dérivés de 2-ureido-benzamide |
JP8533007A JPH10506922A (ja) | 1995-05-05 | 1996-04-27 | 2−ウレイド−ベンズアミド誘導体 |
HU9700005A HUP9700005A3 (en) | 1995-05-05 | 1996-04-27 | 2-ureido-benzamide derivatives and pharmaceutical compositions containing them as active agent |
CA002194481A CA2194481A1 (fr) | 1995-05-05 | 1996-04-27 | Derives de 2-ureido-benzamide |
PCT/EP1996/001836 WO1996034856A1 (fr) | 1995-05-05 | 1996-04-27 | Derives de 2-ureido-benzamide |
EP96914173A EP0769007A1 (fr) | 1995-05-05 | 1996-04-27 | Derives de 2-ureido-benzamide |
US08/765,314 US5872115A (en) | 1995-05-05 | 1996-04-27 | 2-ureido-benzamide derivatives |
AU57635/96A AU5763596A (en) | 1995-05-05 | 1996-04-27 | 2-ureido-benzamide derivatives |
TW085105289A TW318830B (fr) | 1995-05-05 | 1996-05-03 | |
NO965459A NO965459L (no) | 1995-05-05 | 1996-12-18 | 2-ureido-benzamidderivater |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95401049A EP0742208A1 (fr) | 1995-05-05 | 1995-05-05 | Dérivés de 2-ureido-benzamide |
Publications (1)
Publication Number | Publication Date |
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EP0742208A1 true EP0742208A1 (fr) | 1996-11-13 |
Family
ID=8221487
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95401049A Withdrawn EP0742208A1 (fr) | 1995-05-05 | 1995-05-05 | Dérivés de 2-ureido-benzamide |
EP96914173A Withdrawn EP0769007A1 (fr) | 1995-05-05 | 1996-04-27 | Derives de 2-ureido-benzamide |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96914173A Withdrawn EP0769007A1 (fr) | 1995-05-05 | 1996-04-27 | Derives de 2-ureido-benzamide |
Country Status (9)
Country | Link |
---|---|
US (1) | US5872115A (fr) |
EP (2) | EP0742208A1 (fr) |
JP (1) | JPH10506922A (fr) |
AU (1) | AU5763596A (fr) |
CA (1) | CA2194481A1 (fr) |
HU (1) | HUP9700005A3 (fr) |
NO (1) | NO965459L (fr) |
TW (1) | TW318830B (fr) |
WO (1) | WO1996034856A1 (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998004528A2 (fr) * | 1996-07-31 | 1998-02-05 | Bayer Corporation | Pyridines et diphenyles substitues utilises comme agents antihypocholesterolemiques, et antihyperlipoproteinemiques et antihyperglycemiques |
WO2005042488A1 (fr) * | 2003-10-31 | 2005-05-12 | Takeda Pharmaceutical Company Limited | Composes pyridines utilises comme inhibiteurs de dipeptidyle peptidase iv |
WO2009024550A1 (fr) * | 2007-08-20 | 2009-02-26 | N.V. Organon | Dérivés de n-benzyl, n'-arylcarbonylpipérazine |
WO2009138438A1 (fr) * | 2008-05-15 | 2009-11-19 | N.V. Organon | Dérivés de n-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl-n'-arylcarbonylpipérazine |
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WO2007053499A2 (fr) | 2005-11-01 | 2007-05-10 | Millennium Pharmaceuticals, Inc. | Composés pouvant être employés en tant qu'antagonistes de ccr2 |
US7727131B2 (en) * | 2006-03-10 | 2010-06-01 | Brett J. Longo | Linked stretch tubing |
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CN101597278B (zh) | 2008-06-04 | 2013-04-17 | 中国中化股份有限公司 | 酰胺类化合物及其制备与应用 |
WO2017066705A1 (fr) * | 2015-10-14 | 2017-04-20 | Aquinnah Pharmaceuticals, Inc. | Composés, compositions et méthodes d'utilisation contre des granules de stress |
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- 1996-04-27 CA CA002194481A patent/CA2194481A1/fr not_active Abandoned
- 1996-04-27 WO PCT/EP1996/001836 patent/WO1996034856A1/fr not_active Application Discontinuation
- 1996-04-27 JP JP8533007A patent/JPH10506922A/ja not_active Withdrawn
- 1996-04-27 EP EP96914173A patent/EP0769007A1/fr not_active Withdrawn
- 1996-04-27 US US08/765,314 patent/US5872115A/en not_active Expired - Fee Related
- 1996-05-03 TW TW085105289A patent/TW318830B/zh active
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998004528A2 (fr) * | 1996-07-31 | 1998-02-05 | Bayer Corporation | Pyridines et diphenyles substitues utilises comme agents antihypocholesterolemiques, et antihyperlipoproteinemiques et antihyperglycemiques |
WO1998004528A3 (fr) * | 1996-07-31 | 1999-11-11 | Bayer Ag | Pyridines et diphenyles substitues utilises comme agents antihypocholesterolemiques, et antihyperlipoproteinemiques et antihyperglycemiques |
US6218431B1 (en) | 1996-07-31 | 2001-04-17 | Bayer Corporation | Substituted biphenyls |
WO2005042488A1 (fr) * | 2003-10-31 | 2005-05-12 | Takeda Pharmaceutical Company Limited | Composes pyridines utilises comme inhibiteurs de dipeptidyle peptidase iv |
KR100858259B1 (ko) * | 2003-10-31 | 2008-09-11 | 다케다 야쿠힌 고교 가부시키가이샤 | 디펩티딜 펩티다제 iv의 억제제로서의 피리딘 화합물 |
WO2009024550A1 (fr) * | 2007-08-20 | 2009-02-26 | N.V. Organon | Dérivés de n-benzyl, n'-arylcarbonylpipérazine |
CN101848899A (zh) * | 2007-08-20 | 2010-09-29 | 欧加农股份有限公司 | 作为lxr调节剂的n-苄基,n′-芳基羰基哌嗪衍生物 |
US8314091B2 (en) | 2007-08-20 | 2012-11-20 | Msd Oss B.V. | N-benzyl,N'-arylcarbonylpiperazine derivatives |
CN101848899B (zh) * | 2007-08-20 | 2016-03-02 | 默沙东有限责任公司 | 作为lxr调节剂的n-苄基,n′-芳基羰基哌嗪衍生物 |
WO2009138438A1 (fr) * | 2008-05-15 | 2009-11-19 | N.V. Organon | Dérivés de n-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl-n'-arylcarbonylpipérazine |
US8357679B2 (en) | 2008-05-15 | 2013-01-22 | Msd Oss B.V. | Hexafluoroisopropanol derivatives |
CN104262294A (zh) * | 2008-05-15 | 2015-01-07 | 默沙东有限责任公司 | 六氟异丙醇衍生物 |
Also Published As
Publication number | Publication date |
---|---|
NO965459D0 (no) | 1996-12-18 |
HUP9700005A2 (hu) | 1998-05-28 |
JPH10506922A (ja) | 1998-07-07 |
US5872115A (en) | 1999-02-16 |
TW318830B (fr) | 1997-11-01 |
WO1996034856A1 (fr) | 1996-11-07 |
AU5763596A (en) | 1996-11-21 |
CA2194481A1 (fr) | 1996-11-07 |
HUP9700005A3 (en) | 1998-07-28 |
NO965459L (no) | 1996-12-18 |
EP0769007A1 (fr) | 1997-04-23 |
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